Medical Research: What is the background for this study?
Dr. Pawlik: The prognosis of patients operated on for colorectal liver metastasis (CRLM) is currently defined by various “traditional” clinicopathologic factors. However the insight that they provide is incomplete. KRAS is the most common oncogene of the RAS family and is reported in up to 30 to 40% of patients with colorectal liver metastasis. As a result, KRAS mutational status recently attracted a lot of attention as a potential prognostic factor in colorectal liver metastasis. However, overall mutant KRAS status (compared to wild type) correlated with worse survival only in some studies.
We hypothesized that the specific KRAS activating mutations (codon 12 and codon 13) confer different biologic behaviors to the tumor and in turn, account for different (if any) prognostic values. The different proportions of each KRAS specific mutation could determine whether the overall mutational status would be associated with worse survival. In our view, the different proportions of specific mutations in various cohorts could account for the variability of the outcomes in different studies.
Medical Research: What are the main findings?
Dr. Pawlik: Our results showed that only codon 12 KRAS mutations conferred a worse prognosis whereas codon 13 ones did not. Furthermore, we examined the different point mutations that constitute codon 12 mutations and we found that among G12A, G12D, G12V, G12C and G12S KRAS point mutations, only G12V and G12S were independent prognostic factors of worse survival. That confirmed our hypothesis that only some of the point mutations do have a significant prognostic role and that the relative incidence of those mutations could determine if overall KRAS mutational status would be associated with worse survival in a certain cohort.
Medical Research: What should clinicians and patients take away from your report?
Dr. Pawlik: The results of the current study suggest that specific KRAS mutations should be assessed in order to define a more precise prognosis for our patients. In our view, KRAS specific mutations should replace overall KRAS mutation status in clinical practice as a much more refined molecular “tool” for prognosis and clinical decision making.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Pawlik: According to the unique tumor principle, different mutations even in a single gene, can shape distinctive biologic behaviors. Thus, it is possible that different KRAS point mutations reflect to different biologic behaviors in many ways that include, but are not limited to their prognostic role. Unraveling the secrets of those specific mutations could lead to significant advances in the clinical management of colorectal liver metastasis as well as other malignancies that harbor KRAS mutations.
MedicalResearch.com Interview with:, Timothy Michael Pawlik, M.D., M.P.H., Ph.D., Chief, Division of Surgical Oncology, Professor of Surgery, & John Hopkins (2015). Only Some KRAS Gene Mutations Linked To Worse Prognosis In Colon Cancer